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S. Hahn



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    MINI 02 - Immunotherapy (ID 92)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI02.04 - Sequential Assessment of DNA Damage Response and PD-L1 Expression in Circulating Tumor Cells of Lung Cancer Patients during Radiotherapy (ID 2511)

      10:45 - 12:15  |  Author(s): S. Hahn

      • Abstract
      • Presentation
      • Slides

      Background:
      Recent evidence suggests that PD-L1 expression can be induced with radiotherapy and may be a mechanism for resistance to radiotherapy and immunotherapy. Sequentially assessing PD-L1 expression on cancer associated cells in circulation during treatment regimens may be a way to assess the efficacy of radiotherapy and immunotherapy in clinical trials. For this feasibility study, we evaluated the association of RAD50 induction, and PD-L1 expression, on CTCs and Cancer Associated Macrophage-Like Cells (CAMLs) in lung cancer patients (pts) before and during radiotherapy to determine expression changes of these markers.

      Methods:
      Eleven pts with stage I-IV lung cancer were included in this pilot study. Three pts received Stereotactic Body Radiation Therapy (SBRT) for stage I disease and 8 other pts received chemoradiation for stage II-IV disease. Baseline blood samples (7.5 ml) were drawn prior to the start of radiotherapy (T0) and a second blood sample was drawn at a follow up visit during radiotherapy; or for three pts, after completing SBRT (T1); for a total of 22 samples. Blood was processed using CellSieve™ microfiltration (Creatv Microtech), stained for cytokeratin 8, 18 & 19 and CD45, and imaged. Using the QUAS-R (Quench, Underivatize, Amine-Strip and Restain) technique to remove fluoresce signal, all cells were restained for RAD50-AlexaFluor550 and PD-L1-AlexaFluor 488, along with DAPI nuclear stain. The RAD50 foci numbers within nuclear regions were quantified. PD-L1 pixel intensity was measured by the ZenBlue software and grouped into 4 IHC groups: 0-negative (pixel average 0-215), 1-low (pixel average 216-300), 2-medium (pixel average 301-750), and 3-high (pixel average 751+).

      Results:
      There was at least one cytokeratin positive cell (i.e. CTC or CAMLs) found in each of the samples. Specifically CTCs were found in 82% of T0 and 64% of T1 samples, and CAMLs were found in 91% of T0 and 100% of T1 samples. RAD50 foci ranged from 0-16 per cell, with an average of 0.69 at T0 that increased to 3.46 at T1 (p=0.002) during radiotherapy. Distinctively, there were 6 pts with greater than 2 fold RAD50 foci increase at T1 and 5 pts with ≤ 2 fold induction. PD-L1 expression ranged from 34-2004 pixel intensity, with an average of 170 at T0 and 336 at T1 (p=0.08). Interestingly, 4 pts had no PD-L1 expression at T0 but an increase to 2 to 3+ at T1, 4 pts with low/no PD-L1 expression remained low at T1, and 3 pts had high PD-L1 expression that remained high or decreased at T1. There was no correlation between RAD50 induction and PD-L1 expression.

      Conclusion:
      Both RAD50 foci and PD-L1 expression were quantifiable in both CTCs and CAMLs, and had variable responses to radiotherapy +/- chemotherapy. These data suggest that sequential tracking of CTCs or immune-related cells from the primary lung tumor is feasible using microfiltration and potentially can serve as predictive biomarkers for cancer therapy.

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    MINI 07 - ChemoRT and Translational Science (ID 110)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      MINI07.04 - Dynamic Changes in Cell-Free Circulating Tumor DNA to Track Tumor Response and Risk of Recurrence in Stage III Non-Small Cell Lung Cancer (ID 2499)

      16:45 - 18:15  |  Author(s): S. Hahn

      • Abstract
      • Presentation
      • Slides

      Background:
      While the curative management of unresectable stage III non-small cell lung cancer (NSCLC) is definitive chemoradiotherapy, clinical outcomes remain poor. Cellular heterogeneity in tumors is correlated with therapeutic resistance and poor prognosis. We hypothesize that tumor-specific mutant allelic frequency in cell-free DNA from plasma quantifies tumor heterogeneity and that tracking allelic evolution via blood from patients during and after treatment can serve as a non-invasive means to monitor treatment response and recurrence.

      Methods:
      Between 2009-2013, 156 patients with unresectable NSCLC who received definitive radiotherapy or chemoradiotherapy were consented to have blood drawn at baseline before starting radiotherapy, once or twice during treatment, and once or twice during follow up visits. Cell-free plasma DNA was sequenced using a cell-free circulating tumor DNA (ctDNA) next generation sequencing (NGS) assay (Guardant360) that uses digital sequencing to report single nucleotide variants (SNVs) in 68 genes and amplifications in 16 genes. This ctDNA assay has high sensitivity (detects 85%+ of the SNVs detected in tissue in advanced cancer patients) and analytic specificity (>99.9999%). Over 670 serial samples were collected from these patients. Here we report the initial analysis of the first 26 patients of this ongoing study.

      Results:
      Among this initial cohort, 23 (88%) had a recurrence (PFS ranged from 1.2 – 27.9 months) and three (12%) had no evidence of recurrence as of last contact (32.8 – 42.8 months post-radiotherapy completion). Twenty-one patients (81%) had ctDNA alterations present pre-radiotherapy, of which six had a classic driver mutation: KRAS G12F x2; KRAS G12S; PIK3CA E545K x2; PIK3CA H1047R. These six patients had significantly shorter PFS compared to patients without a driver mutation present pre-radiotherapy: average PFS of 4.2 months (1.2 - 8.3) vs. 18.6 months (4.4 - 42.8) respectively (p=0.002). All six had the driver mutation disappear during radiotherapy, four had new alterations appear during and/or post-treatment. One patient had the driver mutation reappear in ctDNA post-radiotherapy and had the shortest PFS (1.2 months) of all patients. Ten patients (38%) had no ctDNA alterations present in the post-radiotherapy blood sample and a trend was observed of improved PFS among patients without ctDNA alterations post-treatment (average PFS 52.3 vs. 75.5 months respectively) however this was not statistically significant (p=0.1). Of note, the three patients without evidence of recurrence as of last contact had no ctDNA alterations identified in the post-treatment sample. This trend is anticipated to become significant with larger sample size.

      Conclusion:
      In this interim analysis, we found that the dynamic alterations of specific mutant alleles strongly correlated with clinical response and that persistence of ctDNA mutant allele concentrations post-definitive treatment is likely a marker of early metastatic recurrence. Undetectable ctDNA in post-treatment sample was seen in the three patients with approximately three years of PFS. These initial results suggest that serial ctDNA analysis may be useful to monitor treatment response and identify patients at high risk for early recurrence who may benefit from additional systemic therapy.

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    ORAL 26 - Clinical Trials 2 (ID 127)

    • Event: WCLC 2015
    • Type: Oral Session
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      ORAL26.06 - Prospective Assessment of Proton Therapy for Malignant Pleural Mesothelioma (ID 3071)

      10:45 - 12:15  |  Author(s): S. Hahn

      • Abstract
      • Presentation
      • Slides

      Background:
      Use of radiotherapy (RT) to treat malignant pleural mesothelioma (MPM) has been limited due to reported significant morbidity and risk of fatal pneumonitis when treating large pleural volumes. To date, RT for MPM has generally been limited to palliation, prophylaxis of surgical tract sites, and adjuvant therapy generally after extrapleural pnuemonectomy. Reports of RT for MPM have employed photons and electrons nearly exclusively. Proton therapy (PT) can significantly reduce irradiation to lung and other critical organs, possibly reducing treatment toxicities and enabling novel RT indications. To date, only a single case series of 4 patients has reported on PT for MPM. We report our prospective experience using PT as adjuvant or definitive therapy for MPM and hypothesized that PT will have low rates of esophagitis and pneumonitis, while providing excellent local control.

      Methods:
      All consecutive patients diagnosed with MPM from 2011-2015 and treated at the Penn Mesothelioma and Pleural Program with PT on a prospective registry study were included for this Institutional Review Board-approved analysis. Local control, defined as lack of tumor progression in the RT portal, and overall survival were measured from PT completion to last follow-up or death. Toxicities were scored using CTCAEv4.

      Results:
      Sixteen patients treated to 17 PT courses were included. Patients were predominantly male (81%) and Caucasian (100%) with epithelial histological subtype (82%) and stage III-IV disease (94%). Patients were a median of 69.8 years old at PT start, which was delivered at a median of 11.1 months (range 3.5-69.3 months) after diagnosis. All patients received pemetrexed plus cisplatin or carboplatin prior to (n=15) or concurrent with (n=1) PT. PT was administered as adjuvant therapy following lung-sparing radical pleurectomy (n=8), to sites of gross disease following progression on systemic therapy (n=8), or as initial definitive therapy with concurrent chemotherapy (n=1). Patients were treated to a median dose of 51.75Gy (CGE) in 2.0Gy daily fractions (range 50.0-75.0Gy/1.8-2.5Gy). At a median follow-up of 5 months from PT completion, all patients had durable local control throughout the study period. Five patients died at a median of 5.4 months following PT. Median overall survival for the cohort has not yet been reached, and 6- and 12-month survival rates were 35% and 24%, respectively. No patients experienced grade ≥3 acute or late toxicity. Across the 17 PT courses, acute grade 2 toxicities included radiation dermatitis (n=8), dysphagia/esophagitis (n=4), anorexia (n=3), fatigue (n=2), and cough (n=1). Late grade 2 toxicity included a single patient with radiation pneumonitis (6%). Overall, patients experienced no significant change in ECOG performance score from PT beginning to end (mean 0.82 to 0.88).

      Conclusion:
      This is the largest report of PT for MPM and demonstrated PT is well tolerated with a favorable toxicity profile compared with photon reports. As such, PT may better allow for integration of RT in multimodality therapy for MPM. This study also demonstrated the efficacy of PT, with local control achieved following all 17 treatment courses. Longer follow-up and additional patients are needed to assess late toxicities and overall survival after PT.

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    P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 1
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      P2.01-041 - MD Anderson Oncology Expert Advisor™ System (OEA™): A Cognitive Computing Recommendations Application (App) for Lung Cancer (ID 3106)

      09:30 - 17:00  |  Author(s): S. Hahn

      • Abstract

      Background:
      The OEA[TM] is a clinical support system with a continuous improvement capability. Its objectives are to enable/empower evidence-based decisions/care by disseminating knowledge and expertise to physicians/users tailored to meet the clinical needs of individual patients as if consulting with an expert. Cognitive computing platforms have the potential to disseminate expert knowledge and tertiary level care to patients. This objective is made possible by making available to physicians/providers cognitive computing generated expert recommendations in diagnosis, staging and treatment. The cognitive computing software was trained by MD Anderson experts using currently available consensus guidelines and an iterative feedback process. Here we test the capability of this cognitive computing software program developed at MD Anderson to generate expert recommendations when patients with advanced-stage NSCLC have a targetable molecular aberration.

      Methods:
      We developed a web based prototype of MD Anderson’s Oncology Expert Advisor (OEA[TM]), a cognitive clinical decision support tool powered by IBM Watson. The Watson technology is IBM’s third generation cognitive computing system based on its unique capabilities in natural language processing and deep QA (question-answer). We trained OEA[TM] by loading historical patient cases and assessed the accuracy of targeted treatment suggestions using MD Anderson’s physicians’ decisions as benchmark. A false positive result was defined as a treatment recommendation rendered with high confidence that was non-correct (less optimal), whereas false negative was defined as a correct or more optimal treatment suggestion listed as a low confidence recommendation.

      Results:
      In our preliminary analyses, OEA[TM] demonstrated four core capabilities: 1) Patient Evaluation through interpretation of structured and unstructured clinical data to create a dynamic case summary with longitudinal view of the pertinent events 2) Treatment and management suggestions based on patient profile weighed against consensus guidelines, relevant literature, and MD Anderson expertise, which included approved therapies, genomic based therapies as well as automated matching to appropriate clinical trials at MD Anderson, 3) Care pathway advisory that alerts the user for anticipated toxicities and its early identification and proactive management, and 4) Patient-oriented research functionalities for identification of patient cohorts and hypothesis generation for future potential clinical investigations. Detailed testing continues and the accuracy of standard-of-care (SOC) treatment recommendations of OEA[TM], as well as false positivity and negativity rates will be presented in detail at the meeting.

      Conclusion:
      OEA[TM] is able to generate dynamic patient case summary by interpreting structured and unstructured clinical data and suggest personalized treatment options. Live system evaluation of OEA[TM] is ongoing and the application of OEA[TM] in clinical practice is expected to be piloted at our institution.

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    P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      P3.03-032 - MD Anderson Oncology Expert Advisor™: A Cognitive Clinical Decision Support Tool for Evidence-Based Multi-Disciplinary Lung Cancer Care (ID 3039)

      09:30 - 17:00  |  Author(s): S. Hahn

      • Abstract
      • Slides

      Background:
      The majority of patients diagnosed with non-small cell lung cancer (NSCLC) receive care in the community setting with limited access to multidisciplinary management common in tertiary care centers. The availability of genomics allows tailored treatments for patients; and with novel, rapidly emerging therapeutic options, it is challenging for busy clinicians to maintain familiarity with current therapy recommendations. Therefore, to empower practicing oncologists in community settings to offer the optimal management at the first intervention, we have developed the MD Anderson Oncology Expert Advisor™ (OEA) application for multi-disciplinary management of lung cancer patients. As the first multi-disciplinary solution for providing comprehensive management of lung cancer, the objective of OEA™ Lung is to leverage cognitive analytics on vast and ever evolving clinical care information and patient big data to disseminate knowledge and expertise, thus enabling physicians to provide evidence-based care and management tailored for the individual patient, similar to consulting an expert. Further, we aimed to create a system for sharing knowledge from more experienced experts to provide care pathways and management recommendations for physicians globally.

      Methods:
      Using cognitive computing, our cancer center partnered with IBM Watson to develop an expert system designed to provide physicians with the tools needed to process high-volume patient and medical information and to stay up-to-date with the latest treatment and management options, so that they can make the best evidence-based treatment decisions for their lung cancer patients. The OEA™ application for lung was built upon core capabilities of the OEA™ applications for leukemia and molecular/targeted therapies. Experts in multiple disciplines including thoracic surgery, medical oncology, and radiation oncology met regularly to design and provide specialized input to the IBM technical team in an agile development cycle. This system was powered to utilize both structured and unstructured data from validated sources; to thoroughly evaluate and stage patients; and to offer eligible clinical trials and personalized therapeutic options. In addition to delivering evidence-based, weighted therapy recommendations, OEA™ Lung provides care pathways for management of toxicities for each treatment modality (surgery, radiation, and medical oncology).

      Results:
      The OEA™ Lung application supports three core functions: 1) dynamic patient summary assimilating complete (structured and unstructured) data to show demographics, labs, genotype, treatment history, and previous treatment responses; 2) weighted evidence-based, multimodality treatment options, with recommendations based on literature support which is provided, along with screening for relevant trials; 3) care pathway advisories, to manage treatment related toxicities for each modality. Further, this product improves quality of care by optimizing outcomes with access to trials and care pathways.

      Conclusion:
      The OEA™ application for lung is a cognitive expert system designed to assimilate multidisciplinary recommendations for care and management of lung cancer patients based on current consensus guidelines and expert recommendations from a quaternary referral cancer center to the community practice setting. By democratizing knowledge from our specialty cancer center, we have taken steps toward achieving an important goal of ending cancer for all, by providing global access to optimal cancer care for patients with this disease. Further evaluation of outcomes following implementation are warranted.

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